The entry of calcium into the mitochondria is fundamentally important in regulating bioenergetic capacity and modulating cell death thresholds. For nearly fifty years, mitochondria were known to have a selective calcium-selective pore in the inner mitochondrial membrane. Entry of calcium through this pore, often termed the calcium uniporter, was believed to be essential in boosting ATP production by augmenting the activity of multiple calcium-sensitive mitochondrial matrix enzymes. This increase in mitochondrial calcium therefore allowed for a rapid but regulated increase in mitochondrial ATP under conditions of increased energetic demand. While under these conditions, the entry of calcium appears beneficial, additional evidence suggested that excessive calcium entry triggers a mitochondrial cell death program characterized by opening of the mitochondrial permeability transition pore (mPTP). Such situations appear to be particularly relevant to tissue injury occurring in the setting of ischemia-reperfusion injury. While considerable electrophysiological, biophysical and physiological data existed on the mitochondrial inner membrane calcium pore, its molecular identity remained elusive for over fifty years. That situation has demonstrably changed in the last five years with the rapid identification of the components of the inner mitochondrial calcium uniporter complex (MCUC) now known to be composed of at least four proteins. These components include the pore- forming protein MCU, its apparent membrane scaffold EMRE and two calcium-sensitive regulators MICU1 and MICU2. The molecular identity of the MCUC paved the way for the creation of mouse models in which one or more component of the complex has been deleted. This, in turn, allows for a more detailed and precise analysis of the physiological role of mitochondrial calcium in regulating both bioenergetics and cell death. Here, we propose to analyze the role of the MCUC in basal and stress-induced cardiovascular physiology. Our particular emphasis will be on the role of the MCUC in ischemia/reperfusion injury, metabolism and aging. This analysis, we believe, will increase our fundamental understanding of both mitochondrial biology and cardiac physiology and potentially pave the way for new treatment strategies targeting a diverse array of conditions ranging from reperfusion injury to the age- dependent decline in cardiac function.